The process of induction and progression of human cancer is exceedingly complex and epidemiologic data suggest the involvement of a multitude of factors. Viral infection years prior to the development of the neoplasm may be one of several precipitating factors. Cellular oncogene activation, secondary to genetic alteration, is another factor believed to be important in human malignancies. The specific aims of this research proposal are to test the hypothesis that viral infection is related to an increased risk of cancer(s) of the head and neck, and to discover the relationship between activated oncogenes and these same cancers. The investigation will take the form of a case-control study. The study population will consist of approximately 1200 patients from physicians in the Departments of Otolaryngology, Surgery, Medicine and Dentistry at Long Island Jewish-Hillside Medical Center. Cases (600) will be patients who are newly diagnosed and treated for: squamous cell carcinomas of the oral cavity, oropharynx, nasopharynx, hypopharynx, larynx, adeno and squamous cell carcinomas of the esophagus, lymphomas of the head and neck, or malignant salivary gland tumors. Controls (600) will be patients surgically treated for benign diseases of the same sites. The occurrence of past infection will be ascertained by: history, serology and biochemical analysis of tissues obtained for the presence of the viral genome and RNA transcripts by Southern blots, DNA/RNA dot blot and in situ hybridizations to molecularly cloned viral DNA probes, and viral capsid and nuclear antigens by immunoperoxidase antibody staining of frozen sections and impression smears. If novel human papillomavirus-related sequences are identified, we will attempt to clone the viral DNA molecule. The presence of activated oncogenes will be studied biochemically by RNA dot blot, Northern blot and in situ hybridizations to molecularly cloned oncogene probes. The two sections of the project - looking for viral and oncogene involvement will be done concurrently. If funded, this would be the first large-scale case-control epidemiologic study of cancers of the head and neck at the biochemical level and would provide objective evidence which should help in evaluating whether a viral etiology and/or known oncogenes are involved. In a broader sense, this information will contribute to our understanding of the interactions between human viruses and oncogenes and cancer.